Publications by authors named "Masatoshi Kudo"

910 Publications

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.

J Clin Oncol 2021 Jul 22:JCO2003555. Epub 2021 Jul 22.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).

Patients And Methods: Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles.

Results: A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively.

Conclusion: All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
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http://dx.doi.org/10.1200/JCO.20.03555DOI Listing
July 2021

Efficacy of endoscopic ultrasound-guided fine-needle aspiration for esophageal schwannoma.

Ann Gastroenterol 2021 Jul-Aug;34(4):597. Epub 2021 Jun 3.

Department of Gastroenterology and Hepatology (Shigenaga Matsui, Tomohiro Yamazaki, Masatoshi Kudo).

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http://dx.doi.org/10.20524/aog.2021.0636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276371PMC
June 2021

Integrative analysis of gut microbiome and host transcriptomes reveals associations between treatment outcomes and immunotherapy-induced colitis.

Mol Oncol 2021 Jul 16. Epub 2021 Jul 16.

Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, 377-2 Osaka-Sayama, Osaka, 589-8511, Japan.

Immune checkpoint inhibitors (ICIs) are widely used to treat various malignancies. Although the gut microbiome is known to influence the efficacy of ICIs on epithelial tumors, the functional interactions between gut taxa and colonic mucosa remain poorly understood. Here we performed transcriptomic profiling and 16S rRNA sequencing to investigate the relationships between mucosal gene expression and microbial composition with ICI responses and gastrointestinal immune-related adverse events (GI irAEs). In responders, genes related to DNA repair and cell cycle signatures were enriched in responders whereas signatures related to innate immune response, NFAT and IFN-γ signaling pathways were enriched in non-responders. Gut microbial composition revealed an association between moderate GI irAE and favorable response to ICI therapy. Favorable therapeutic responses to ICI and GI irAE treatments were associated to taxa classified as Enterobacteriaceae and were related to ribonucleoprotein complex biogenesis, cytokine-mediated signaling pathway, tRNA metabolic process and ribonucleoprotein complex assembly in the colon. These findings open new perspectives for improving the efficacy and safety of cancer immunotherapy.
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http://dx.doi.org/10.1002/1878-0261.13062DOI Listing
July 2021

Can the Entire Ablative Hyperechoic Zone be Regarded as a Necrotic Lesion After Radiofrequency Ablation of the Liver?

Ultrasound Med Biol 2021 Jul 13. Epub 2021 Jul 13.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

Developments in image fusion technology made it possible to visualize the ablative margin on ultrasound (US). The purpose of the present study was to assess the ablative area of radiofrequency ablation for hepatocellular carcinoma and compare it with the ablative hyperechoic zone with a non-enhanced area on contrast-enhanced US/contrast-enhanced computed tomography (CEUS/CECT) in the same cross-section. This retrospective study included 25 patients with 27 hepatocellular carcinomas. The long and short dimensions of the ablative hyperechoic zone were measured using B-mode US, and those of the non-enhanced area were assessed with CEUS/CECT on the same cross-section measured with B-mode US, using image fusion techniques. The technical effectiveness of ablation with an adequate ablative margin in a single session was determined in all patients. The long and short dimensions of the ablative hyperechoic zone ranged between 15.0 and 40.7 mm (mean: 27.3 ± 6.9 mm) and between 14.0 and 33.0 mm (mean: 23.3 ± 5.8 mm), respectively. R values for the long and short dimensions were 0.99 and 0.98, respectively, between B-mode US and CEUS, and 0.96 and 0.92, respectively, between B-mode US and CECT. The ablative hyperechoic zone may be regarded as a necrotic lesion after radiofrequency ablation.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.05.004DOI Listing
July 2021

Immunohistochemical characterization of granulomatosis with polyangiitis exhibiting spontaneous regression.

Asian Pac J Allergy Immunol 2021 Jul 11. Epub 2021 Jul 11.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Background: Granulomatosis with polyangiitis (GPA) is characterized by granulomatous inflammation, vasculitis, and elevated levels of serum proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibody (PR3-ANCA).

Objective: We tried to characterize immune cells accumulated into the lung lesions of a GPA patient exhibiting spontaneous regression.

Methods: Transbronchial lung biopsy (TBLB) samples were subjected to immunohistochemical analyses.

Results: Multiple lung nodules were detected by CT. TBLB showed granulomatous inflammation and small vessel vasculitis. This case was diagnosed as GPA based on pathological findings and elevation of PR-3 ANCA levels. Spontaneous disappearance of multiple lung nodules was observed in CT. CD3+ T cells and CD20+ B cells accumulated in the inflammatory lesions surrounding the vessels whereas granulomatous inflammation was mainly comprised of CD3+ T cells and CD68+ macrophages, but not B cells or myeloperoxidase+ neutrophils.

Conclusions: We characterized immune cell compositions of the lung lesions of a patient with GPA exhibiting spontaneous regression.
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http://dx.doi.org/10.12932/AP-190221-1073DOI Listing
July 2021

Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: A Subgroup Analysis of Asian Patients in the Phase 3 KEYNOTE-240 Trial.

Liver Cancer 2021 Jun 27;10(3):275-284. Epub 2021 Apr 27.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Introduction: KEYNOTE-240 investigated the efficacy and safety of pembrolizumab plus best supportive care (BSC) in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). Results for the subgroup of patients from Asia are described.

Methods: Adults with advanced HCC previously treated with sorafenib were randomized 2:1 to pembrolizumab or placebo plus BSC. Here, the Asian subgroup comprised patients enrolled in Hong Kong, Japan, Korea, the Philippines, Taiwan, and Thailand. Primary endpoints were progression-free survival (PFS) per blinded central imaging review and overall survival (OS). Secondary endpoints included objective response rate (ORR) per blinded central imaging review, duration of response (DOR), and safety.

Results: The Asian subgroup included 157 patients. As of January 2, 2019, the median follow-up in this subgroup was 13.8 months for pembrolizumab and 8.3 months for placebo. The median PFS was 2.8 months for pembrolizumab (95% confidence interval [CI] 2.6-4.1) versus 1.4 months (95% CI 1.4-2.4) for placebo (hazard ratio [HR] 0.48; 95% CI 0.32-0.70). The median OS was 13.8 months (95% CI 10.1-16.9) for pembrolizumab versus 8.3 months (95% CI 6.3-11.8) for placebo (HR 0.55; 95% CI 0.37-0.80). ORR was 20.6% (95% CI 13.4-29.5) for pembrolizumab versus 2.0% (95% CI 0.1-10.6) for placebo (difference: 18.5%; 95% CI 8.3-27.6). The median DOR was 8.6 and 2.8 months for pembrolizumab and placebo, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 63 patients (58.9%) receiving pembrolizumab and 24 patients (48.0%) receiving placebo; 14 (13.1%) and 2 (4.0%) patients experienced grade 3-5 TRAEs, respectively. No treatment-related deaths occurred.

Conclusion: Pembrolizumab demonstrated antitumor activity and was well tolerated in the Asian subgroup of KEYNOTE-240. A trend toward greater benefit with pembrolizumab in the Asian subgroup was observed compared with the overall cohort, supporting further evaluation of pembrolizumab treatment in this population.
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http://dx.doi.org/10.1159/000515553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237794PMC
June 2021

Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial.

Liver Cancer 2021 Jun 7;10(3):249-259. Epub 2021 Apr 7.

Faculty of Medicine, Kyorin University, Tokyo, Japan.

Introduction: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC.

Methods: Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC.

Results: Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension ( = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome ( = 5 [22.7%]), and decreased appetite ( = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9-34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9-54.9%) per mRECIST for HCC.

Conclusion: Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.
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http://dx.doi.org/10.1159/000514420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237783PMC
June 2021

Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update.

Liver Cancer 2021 Jun 19;10(3):181-223. Epub 2021 May 19.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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http://dx.doi.org/10.1159/000514174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237791PMC
June 2021

Surveillance, Diagnosis, and Treatment Outcomes of Hepatocellular Carcinoma in Japan: 2021 Update.

Authors:
Masatoshi Kudo

Liver Cancer 2021 Jun 25;10(3):167-180. Epub 2021 May 25.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

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http://dx.doi.org/10.1159/000516491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237798PMC
June 2021

Efficacy of Over-The-Scope Clip Method as a Novel Hemostatic Therapy for Colonic Diverticular Bleeding.

J Clin Med 2021 Jun 29;10(13). Epub 2021 Jun 29.

Departments of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.

Colonic diverticular could bleed recurrently, and, sometimes, fatal massive bleeding could occur. However, the choice of endoscopic hemostasis remains controversial. Although the over-the-scope clip (OTSC) method has been reported to be effective, it has not been fully evaluated due to the small number of cases. This study aimed to evaluate the efficacy of the OTSC method for colonic diverticular bleeding. Between August 2017 and December 2020, 36 consecutive patients, including those who could not be treated using endoscopic band ligation (EBL) and those in whom re-bleeding had occurred after EBL, underwent the OTSC method for hemostasis of colonic diverticular bleeding at Hyogo Prefectural Awaji Medical Center. The procedure success rate, adverse events rate, early phase re-bleeding rate (within 30 days following primary hemostasis), and the requirement rate for additional transcatheter arterial embolization (TAE) or surgery were the outcomes assessed. The outcomes were procedure success rate 100%, adverse events rate 0%, early phase re-bleeding rate 8.3%, and additional TAE or surgery rate 0%. These results suggest that the OTSC method is a safe and effective treatment for managing colonic diverticular bleeding.
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http://dx.doi.org/10.3390/jcm10132891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268121PMC
June 2021

Usefulness of the Novel Snare-over-the-Guidewire Method for Transpapillary Plastic Stent Replacement (with Video).

J Clin Med 2021 Jun 28;10(13). Epub 2021 Jun 28.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan.

Unsuccessful stent replacement in transpapillary biliary drainage with plastic stents (PSs) has a significant impact on patient prognosis; thus, a safe and reliable replacement method is required. We aimed to compare the snare-over-the-guidewire (SOG) method, wherein the PS lumen is used as an access route to the biliary tract and the PS is removed with a snare inserted via the inserted guidewire, with the conventional side-of-stent (SOS) method, wherein the biliary approach is performed from the side of the PS. This retrospective single-center study included 244 consecutive patients who underwent biliary PS replacement between January 2018 and July 2020. The procedural success rates were compared between the two methods. A predictive analysis of unsuccessful PS replacement was also performed. The procedural success rate in the SOG group was significantly higher than that in the SOS group ( = 0.026). In the proximal biliary stenosis lesion, the same trend was observed ( = 0.025). Multivariate analysis also showed that the SOS method ( = 0.0038), the presence of proximal biliary stenosis ( < 0.0001), and parapapillary diverticulum ( = 0.0007) were predictors of unsuccessful PS replacement. The SOG method may be useful for biliary PS replacement, especially in cases of proximal hilar bile duct stenosis.
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http://dx.doi.org/10.3390/jcm10132858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268235PMC
June 2021

NOD2 deficiency protects mice from the development of adoptive transfer colitis through the induction of regulatory T cells expressing forkhead box P3.

Biochem Biophys Res Commun 2021 Jun 25;568:55-61. Epub 2021 Jun 25.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor for muramyl dipeptide derived from the intestinal microbiota. Loss-of-function mutations in Nod2 are associated with the development of Crohn's disease, suggesting that NOD2 signaling plays critical roles in the maintenance of intestinal immune homeostasis. Although NOD2 activation prevents the development of short-term experimental colitis, it remains unknown whether the sensitivity to long-term experimental colitis is influenced by NOD2. In this study, we explored the roles played by NOD2 in the development of long-term adoptive transfer colitis. Unexpectedly, we found that Rag1Nod2 mice were more resistant to adoptive transfer colitis than Rag1 mice and had reduced proinflammatory cytokine responses and enhanced accumulation of regulatory T cells (Tregs) expressing forkhead box P3 in the colonic mucosa. Prevention of colitis in Rag1Nod2 mice was mediated by TGF-β1 because neutralization of TGF-β1 resulted in the development of more severe colitis due to reduced accumulation of Tregs. Such paradoxical Treg responses in the absence of NOD2 could explain why Nod2 mutations in humans are not sufficient to cause Crohn's disease.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.068DOI Listing
June 2021

Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease etiology.

Liver Int 2021 Jun 26. Epub 2021 Jun 26.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Background & Aims: Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying etiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease etiology and baseline serum viral load.

Methods: Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N=542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by etiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pretreatment serum HBV-DNA and HCV-RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study).

Results: Baseline characteristics were generally balanced between arms in each subgroup (HBV: N=225, HCV: N=127, Other: N=190). No significant difference in treatment effect by etiology subgroup was detected (OS interaction p-value= 0.23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74; 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82; 95% CI 0.55-1.23) for HCV, and 8.5 versus 5.4 (HR 0.56; 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function, and liver-specific adverse events.

Conclusions: Ramucirumab improved survival across etiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.
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http://dx.doi.org/10.1111/liv.14994DOI Listing
June 2021

Artificial intelligence-based endoscopic diagnosis of colorectal polyps using residual networks.

PLoS One 2021 22;16(6):e0253585. Epub 2021 Jun 22.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

Convolutional neural networks (CNNs) are widely used for artificial intelligence (AI)-based image classification. Residual network (ResNet) is a new technology that facilitates the accuracy of image classification by CNN-based AI. In this study, we developed a novel AI model combined with ResNet to diagnose colorectal polyps. In total, 127,610 images consisting of 62,510 images with adenomatous polyps, 30,443 with non-adenomatous hyperplastic polyps, and 34,657 with healthy colorectal normal mucosa were subjected to deep learning after annotation. Each validation process was performed using 12,761 stored images of colorectal polyps by a 10-fold cross validation. The efficacy of the ResNet system was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy. The sensitivity, specificity, PPV, NPV, and diagnostic accuracy for adenomatous polyps at WLIs were 98.8%, 94.3%, 90.5%, 87.4%, and 92.8%, respectively. Similar results were obtained for adenomatous polyps at narrow-band imagings (NBIs) and chromoendoscopy images (CEIs) (NBIs vs. CEIs: sensitivity, 94.9% vs. 98.2%; specificity, 93.9% vs. 85.8%; PPV, 92.5% vs. 81.7%; NPV, 93.5% vs. 99.9%; and overall accuracy, 91.5% vs. 90.1%). The ResNet model is a powerful tool that can be used for AI-based accurate diagnosis of colorectal polyps.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253585PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219125PMC
June 2021

Novel troubleshooting technique for the migration of a biliary plastic stent using a thin balloon catheter (with video).

J Hepatobiliary Pancreat Sci 2021 Jun 15. Epub 2021 Jun 15.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

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http://dx.doi.org/10.1002/jhbp.1006DOI Listing
June 2021

Case Report: Concurrent Occurrence of Abdominal Double Expressor Lymphoma and Jejunum Follicular Lymphoma.

Front Oncol 2021 26;11:656219. Epub 2021 May 26.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Double expressor lymphoma (DEL), defined as overexpression of BCL2 and MYC, is an aggressive subtype of diffuse large B cell lymphoma (DLBCL). Here we report a case of a 64-year-old female diagnosed with abdominal DEL transformed from jejunum follicular lymphoma (FL). 18F-fluorodeoxyglucose (FDG)-positron emission tomography showed diffuse accumulation of FDG into the peritoneum and small bowel wall. Double balloon-assisted enteroscopy revealed whitish submucosal tumors in the proximal jejunum. Aggregation of atypical lymphocytes positive for CD20, CD79a, and BCL2 was seen in the jejunal biopsy samples. These atypical lymphocytes were monoclonal since cell surface expression of Ig light chains was limited to κ chain by flow-cytometry. Thus, immunohistochemical and flowcytometric analyses data were consistent with FL of the jejunum. Neoplastic lymphocytes obtained from ascites were positive for CD10, CD20, CD79a, BCL2, and BCL6. Fluorescence hybridization (FISH) showed formation of fusion gene and extra copies of , the former of which is a characteristic chromosomal abnormality of FL. These genetic alterations and protein expression profiles of ascitic fluid cells were consistent with those of DEL transformed from FL. Given that a significant population of patients with indolent FL of the gastrointestinal tract developed into aggressive DLBCL, it is likely that primary FL of the jejunum transformed into the abdominal aggressive DEL in this case. This case is unique in that concurrent occurrence of FL and DEL was confirmed by immunohistochemical and FISH analyses and that abdominal DEL transformed from jejunal FL was highly suspected.
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http://dx.doi.org/10.3389/fonc.2021.656219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187768PMC
May 2021

Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma: Early clinical experience.

Cancer Rep (Hoboken) 2021 Jun 11:e1464. Epub 2021 Jun 11.

Department of Internal Medicine, Himeji Red Cross Hospital, Hyogo, Japan.

Background: Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u-HCC), changes in hepatic function during therapy have yet to be reported.

Aim: This retrospective clinical study aimed to elucidate early responses to Atez/Bev.

Methods: From September 2020 to April 2021, 171 u-HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin-bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively.

Results: In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR-6W/DCR-6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR-6W/DCR-6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post-progression treatment following lenvatinib (ORR-6W/DCR-6W = 7.7%/79.5%), for which no known effective post-progression treatment has been established. In 111 patients who underwent a 6-week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (-2.525 ± 0.419 vs -2.323 ± 0.445, p < .001), but then recovered at 6-weeks (-2.403 ± 0.452) as compared to 3-weeks (p = .001). During the observation period, the most common adverse events were appetite loss (all grades) (12.3%), general fatigue/hypertension (all grades) (11.1%, respectively), and urine protein (all grades) (10.5%).

Conclusion: Atez/Bev might have therapeutic potential not only as first but also later-line treatment of existing molecular target agents. In addition, this drug combination may have less influence on hepatic function during the early period, as the present patients showed a good initial therapeutic response.
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http://dx.doi.org/10.1002/cnr2.1464DOI Listing
June 2021

Cumulative radiation doses from recurrent PET/CT examinations.

Br J Radiol 2021 Jul 8:20210388. Epub 2021 Jul 8.

Department of Radiation Oncology, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, Japan.

Positron emission tomography (PET)/CT is an essential imaging modality for the management of various diseases. Increasing numbers of PET/CT examinations are carried out across the world and deliver benefits to patients; however, there are concerns about the cumulative radiation doses from these examinations in patients. Compared to the radiation exposure delivered by CT, there have been few reports on the frequency of patients with a cumulative effective radiation dose of ≥100 mSv from repeated PET/CT examinations. The emerging dose tracking system facilitates surveys on patient cumulative doses by PET/CT because it can easily wrap up exposure doses of PET radiopharmaceuticals and CT. Regardless of the use of a dose tracking system, implementation of justification for PET/CT examinations and utilisation of dose reduction measures are key issues in coping with the cumulative dose in patients. Despite all the advantages of PET/MRI such as eliminating radiation exposure from CT and providing good tissue contrast in MRI, it is expensive and cannot be introduced at every facility; thus, it is still necessary to utilise PET/CT with radiation reduction measures in most clinical situations.
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http://dx.doi.org/10.1259/bjr.20210388DOI Listing
July 2021

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

Clin Cancer Res 2021 Jun 9. Epub 2021 Jun 9.

Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.

Purpose: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT.

Experimental Design: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated.

Results: Four hundred and seven patients were included in the serum analysis set (lenvatinib = 279, sorafenib = 128); 58 patients were included in the gene-expression analysis set (lenvatinib = 34, sorafenib = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, = 0.014; FGF23: 48.4% vs. 16.4%, = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; = 0.0253).

Conclusions: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4219DOI Listing
June 2021

Comparison of radiation exposure between endoscopic ultrasound-guided drainage and transpapillary drainage by endoscopic retrograde cholangiopancreatography for pancreatobiliary diseases.

Dig Endosc 2021 Jun 9. Epub 2021 Jun 9.

Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka-sayama, Osaka, Japan.

Objectives: The transpapillary drainage by endoscopic retrograde cholangiopancreatography (ERCP-D) cannot be performed without fluoroscopy, and there are many situations in which fluoroscopy is required even in endoscopic ultrasound-guided drainage (EUS-D). Previous studies have compared the efficacy, but not the radiation exposure of EUS-D and ERCP-D. While radiation exposure in ERCP-D has been previously evaluated, there is a paucity of information regarding radiation doses in EUS-D. This study aimed to assess radiation exposure in EUS-D compared with that in ERCP-D.

Methods: This retrospective single-center cohort study included consecutive patients who underwent EUS-D and ERCP-D between October 2017 and March 2019. The air kerma (AK: mGy), kerma-area product (KAP: Gycm ), fluoroscopy time (FT: min), and procedure time (PT: min) were assessed. The invasive probability weighting method was used to qualify the comparisons.

Results: We enrolled 372 and 105 patients who underwent ERCP-D and EUS-D, respectively. The mean AK, KAP, and FT in the EUS-D group were higher by 53%, 28%, and 27%, respectively, than those in the ERCP-D group, whereas PT was shorter by approximately 11% (AK; 135.0 vs. 88.4, KAP; 28.1 vs. 21.9, FT; 20.4 vs. 16.0, PT; 38.7 vs. 43.5). The sub-analysis limited to biliary drainage cases showed the same trend (AK; 128.3 vs. 90.9, KAP; 27.0 vs. 22.2, FT; 16.4 vs. 16.1, PT; 32.5 vs. 44.4).

Conclusions: This is the first study to assess radiation exposure in EUS-D compared with that in ERCP-D. Radiation exposure was significantly higher in EUS-D than in ERCP-D, despite the shorter procedure time.
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http://dx.doi.org/10.1111/den.14060DOI Listing
June 2021

Nontraumatic tube method for detecting a vessel responsible for colonic diverticular hemorrhage.

Endoscopy 2021 Jun 8. Epub 2021 Jun 8.

Departments of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Sayama, Osaka, Japan.

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http://dx.doi.org/10.1055/a-1486-6476DOI Listing
June 2021

Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial.

Lancet Gastroenterol Hepatol 2021 Aug 2;6(8):649-658. Epub 2021 Jun 2.

FSBSI N N Blokhin Russian Cancer Research Center, Moscow, Russia.

Background: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL.

Methods: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266.

Findings: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months.

Interpretation: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma.

Funding: Eisai and Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S2468-1253(21)00110-2DOI Listing
August 2021

Case Report: A Case of Intestinal Behçet's Disease Exhibiting Enhanced Expression of IL-6 and Forkhead Box P3 mRNA After Treatment With Infliximab.

Front Med (Lausanne) 2021 14;8:679237. Epub 2021 May 14.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

Behçet's disease (BD) is a rare inflammatory condition characterized by oral and genital ulcers, skin lesions, as well as ophthalmological, neurological, and gastrointestinal manifestations. BD involving the gastrointestinal tract is known as intestinal BD. The mucosa of the gastrointestinal tract of patients with intestinal BD exhibits enhanced levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These proinflammatory cytokines play pathogenic roles in the development of BD, as evidenced by the fact that biologics targeting these cytokines effectively induce BD remission. It should be noted, however, that the molecular mechanisms by which the blockade of these cytokines suppresses chronic inflammatory responses in BD are poorly understood. Herein, we report a case of intestinal BD resistant to prednisolone that was successfully treated with infliximab (IFX). The induction of remission by IFX was accompanied by a marked elevation of IL-6 and forkhead box P3 (FOXP3) at mRNA level. This case suggests that induction of remission by IFX is mediated not only by the suppression of TNF-α-mediated signaling pathways, but also by the promotion of IL-6 expression and accumulation of regulatory T cells expressing FOXP3.
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http://dx.doi.org/10.3389/fmed.2021.679237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160115PMC
May 2021

Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial.

Lancet Oncol 2021 07 27;22(7):991-1001. Epub 2021 May 27.

Department of Medical Oncology, Gustave Roussy, Villejuif, France.

Background: Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy.

Methods: We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379.

Findings: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning.

Interpretation: Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma.

Funding: F Hoffmann-La Roche and Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00151-0DOI Listing
July 2021

CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis.

J Hepatol 2021 May 26. Epub 2021 May 26.

Liver Unit, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.

Background & Aims: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status.

Methods: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.

Results: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC.

Conclusions: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC.

Lay Summary: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population.

Clinical Trial Number: NCT01658878.
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http://dx.doi.org/10.1016/j.jhep.2021.04.047DOI Listing
May 2021

Report of the 22nd Nationwide Follow-Up Survey of Primary Liver Cancer in Japan (2012-2013).

Hepatol Res 2021 May 29. Epub 2021 May 29.

Follow-up Survey Committee, Liver Cancer Study Group of Japan, Japan.

In the 22nd Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 21,155 newly registered patients and 43,041 previously registered follow-up patients were compiled from 538 institutions over a 2-year period from 1 January 2012 to 31 December 2013. Basic statistics compiled for patients newly registered in the 22nd survey was cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment-related factors, pathological diagnosis, recurrence status, and autopsy findings. Compared with the previous 21st survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, had more patients with non-B non-C HCC, had smaller tumor diameter, and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2002 and 2013 whose final outcome was survival or death. Median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, or Child-Pugh grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2013 into five time period groups. The data obtained from this nationwide follow-up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer in the world. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/hepr.13675DOI Listing
May 2021

Impact of hepatitis C virus on survival in patients undergoing resection of intrahepatic cholangiocarcinoma: Report of a Japanese nationwide survey.

Hepatol Res 2021 May 26. Epub 2021 May 26.

Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Aim: We reviewed the data of a nationwide follow-up survey to determine the impact of hepatitis C virus (HCV) infection on the outcomes of hepatectomy for mass-forming (MF) type, and combined mass-forming and periductal infiltrating (MF + PI) type intrahepatic cholangiocarcinoma (ICC).

Methods: In total, 956 patients with ICC who underwent curative hepatic resection were included in this cohort study, and patients were classified according to virus status. Patients were classified according to virus status as follows: HCV-related ICC (n = 138, 14.4%), hepatitis B virus (HBV)-related ICC (n = 43, 4.5%) and non-virus-related ICC (n = 775, 81.1%). To control for variables, we used 1:1 propensity score-matching to compare outcomes after surgery between HCV-related (n = 102) and non-virus-related ICC cases (n = 102).

Results: We successfully matched HCV-related and non-virus-related ICC cases with similar liver function and tumor characteristics. Patients with HCV-related ICC had significantly shorter recurrence-free survival (hazard ratio 0.62, 95% confidence interval 0.42-0.92, p = 0.016) and overall survival (hazard ratio: 0.57, 95% confidence interval: 0.37-0.88, p = 0.011) than patients with non-virus-related ICC. Cox proportional hazard analysis showed that HCV-related ICC offered a worse prognosis than non-virus-related ICC.

Conclusions: HCV infection increases the risk of recurrence and worsens overall survival in patients after curative resection for MF and combined MF + PI type ICC.
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http://dx.doi.org/10.1111/hepr.13676DOI Listing
May 2021

Biomarkers in autoimmune pancreatitis and immunoglobulin G4-related disease.

World J Gastroenterol 2021 May;27(19):2257-2269

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.

Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.
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http://dx.doi.org/10.3748/wjg.v27.i19.2257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130041PMC
May 2021

Therapeutic efficacy of ramucirumab after lenvatinib for post-progression treatment of unresectable hepatocellular carcinoma.

Gastroenterol Rep (Oxf) 2021 Apr 10;9(2):133-138. Epub 2020 Oct 10.

Gastroenterology Center, Ehime Prefectural Central Hospital, Ehime, Japan.

Background: Lenvatinib is used for unresectable hepatocellular carcinoma (u-HCC) as first-line, as well as second- and third-line therapy in Japan. We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment.

Methods: Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020, 28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner.

Results: The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was -2.19. Of the 28 patients, 23 were male, 21 were classified as Child-Pugh A and 7 as Child-Pugh B, and 25 were Barcelona Clinic Liver Cancer Stage C. Ramucirumab was given as second-line therapy in 14, third-line in 9, and fourth-line in 5. Therapeutic response was obtained in only 26 patients; the objective response rate was 3.8% (1/26) and the disease-control rate was 42.3% (11/26), with a median period to progression of 2.0 months. The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events (gastrointestinal bleeding, ascites) in 2.

Conclusions: The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.
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http://dx.doi.org/10.1093/gastro/goaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128005PMC
April 2021

Antacid exposure and immunotherapy outcomes among patients with advanced hepatocellular carcinoma.

Ther Adv Med Oncol 2021 28;13:17588359211010937. Epub 2021 Apr 28.

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1079, New York, NY 10029, USA.

Background: Antibiotic exposure has been associated with worse outcomes with immune checkpoint inhibitors (ICIs) in cancer patients, likely due to disruption of the gut microbiome. Other commonly prescribed medications, such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs), are also known to disrupt the microbiome, but data on their association with ICI outcomes are conflicting.

Methods: We conducted a retrospective, multicenter, international cohort study including 314 hepatocellular carcinoma (HCC) patients treated with ICIs from 2017 to 2019 to assess the association between PPI or H2RA exposure (up to 30 days before ICI) and overall survival. Secondary outcomes included overall response rate (ORR) and development of any treatment-related adverse events (AEs).

Results: Baseline PPI/H2RA exposure was not associated with overall survival in univariable (HR 1.01, 95% CI 0.75-1.35) or multivariable analysis (HR 0.98, 95% CI 0.71-1.36). Baseline PPI/H2RA exposure was not associated with either ORR (OR 1.32, 95% CI 0.66-2.65) or AEs (OR 1.07, 95% CI 0.54-2.12) in multivariable analysis.

Conclusions: Our results suggest that exposure to PPI/H2RA prior to ICIs does not adversely affect outcomes in HCC patients.
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http://dx.doi.org/10.1177/17588359211010937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107671PMC
April 2021